High frequency stimulation for treating sensory and/or motor deficits in patients with spinal cord injuries and/or peripheral polyneuropathy, and associated systems and methods

ABSTRACT

High frequency stimulation for treating sensory and/or motor deficits in patients with spinal cord injuries and/or peripheral polyneuropathy, and associated systems and methods. A representative method includes addressing the patient&#39;s somatosensory dysfunction and/or motor dysfunction, resulting from neuropathy and/or spinal cord injury, by directing an electrical therapy signal to the patient&#39;s spinal cord region, the therapy signal having a frequency in a frequency range from 1.5 kHz to 100 kHz.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Nonprovisional patentapplication Ser. No. 16/937,463, filed Jul. 23, 2020, which is acontinuation of U.S. Non-Provisional patent application Ser. No.15/874,504, filed Jan. 18, 2018, and claims priority to the following USProvisional Patent Applications: U.S. Provisional Patent Application62/448,320, filed on Jan. 19, 2017; and U.S. Provisional PatentApplication 62/588,185, filed on Nov. 17, 2017; both of which areincorporated herein by reference in their entireties.

TECHNICAL FIELD

The present disclosure is directed generally to high frequencyelectrical stimulation for treating sensory and/or motor deficits inpatients with spinal cord injuries and/or peripheral polyneuropathy, andassociated systems and methods.

BACKGROUND

An estimated 20 million people in the United States have some form ofperipheral neuropathy, a condition that develops as a result of damageto the peripheral nervous system (“PNS”). The PNS is a vastcommunications network that connects the central nervous system (“CNS”)to the limbs and organs, essentially serving as a communication relaygoing back and forth between the brain and spinal cord with the rest ofthe body. Damage to the PNS interferes with this communication pathway,and symptoms can range from numbness or tingling, to pricking sensationsor muscle weakness. Peripheral neuropathy has been conventionallytreated with medication, injection therapy, physical therapy, surgery,and light. More recently, diabetic peripheral neuropathy has beentreated by applying a surface electrical stimulation at a specifiedfrequency to the muscles and nerves. Most treatments are designed totreat the underlying cause of the neuropathy, but in many cases, thecause of the neuropathy is unknown or, even if the cause has beenidentified, a specific treatment may not exist. Accordingly, there is aneed for systems and methods for treating peripheral neuropathy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a partially schematic illustration of an implantable spinalcord modulation system positioned at the spine to deliver therapeuticsignals in accordance with embodiments of the present technology.

FIGS. 2-3 are partially schematic, cross-sectional illustrations of apatient's spine, illustrating representative locations for implantedlead bodies in accordance with embodiments of the present technology.

FIG. 4 is a table showing selected clinical data gathered fromApplicant's clinical study showing treatment of sensory deficit withhigh frequency spinal cord stimulation, in accordance with embodimentsof the present technology.

FIGS. 5A-5C illustrate clinical results for patients treated forperipheral polyneuropathy with high frequency stimulation in accordancewith embodiments of the present technology.

DETAILED DESCRIPTION 1.0 Introduction

The present technology is directed generally to systems and methods fortreating peripheral neuropathy, peripheral polyneuropathy (PPN), painfuldiabetic neuropathy (PDN), dysesthesia, sensory deficits, motordeficits, and/or spinal cord injury using high frequency electricalstimulation. In particular, the systems and methods of the presenttechnology may at least partially restore sensory loss in patientssuffering from peripheral neuropathy and/or other indications. In oneembodiment, the present technology includes improving the patient'ssomatosensory function by delivering an electrical signal, having afrequency of from 1.5 kHz to 100 kHz to the patient's spinal cord via atleast one implantable signal delivery device, and wherein the electricalsignal has a frequency of from 1.5 kHz to 100 kHz.

Definitions of selected terms are provided under heading 1.0(“Definitions”). General aspects of the anatomical and physiologicalenvironment in which the disclosed technology operates are describedbelow under heading 2.0 (“Introduction”). Representative treatmentsystems and associated methods, are described under heading 3.0(“Representative Treatment Systems and Associated Methods”) withreference to FIGS. 1-3 . Representative clinical data generated from theuse of Applicant's treatment systems and methods disclosed herein aredescribed under heading 4.0 (“Representative Clinical Data”) withreference to FIG. 4-5C. The foregoing headings are provided fororganizational purposes only. Features defined and/or described aboveunder any of the foregoing headings may be combined with and/or appliedto features described under any of the other headings, in accordancewith embodiments of the present technology.

2.0 Definitions

As used herein, the terms “high frequency” and “HF” refer to a frequencyof from about 1.2 kHz to about 100 kHz, or from about 1.5 kHz to about100 kHz, or from about 2 kHz to about 50 kHz, or from about 3 kHz toabout 20 kHz, or from about 3 kHz to about 15 kHz, or from about 5 kHzto about 15 kHz, or from about 3 kHz to about 10 kHz, or 1 kHz, 2 kHz, 3kHz, 4 kHz, 5 kHz, 10 kHz, 15 kHz, 20 kHz, 50 kHz, or 100 kHz, unlessotherwise stated. Unless otherwise stated, the term “about” refers tovalues within 10% of the stated value. As used herein, “low frequency”or “LF” refers to a frequency less than 1.2 kHz or less than 1 kHz.

As used herein, “peripheral neuropathy” refers to damage to or diseaseaffecting one or more peripheral nerves or groups of peripheral nerves.Peripheral neuropathy may refer to nerve damage or disease in one nerveor area of the body (mononeuropathy), multiple nerves or multiple areasof the body (polyneuropathy), and/or in the same place on both sides ofthe body (symmetric neuropathy). Representative systems and methods inaccordance with embodiments of the present technology are configured totreat all types of peripheral neuropathy, irrespective of whether it isinherited or acquired. Inherited causes include Charcot-Marie Tooth,Kennedy's disease (X-linked bilbospinal muscular atrophy), Van Allen'sSyndrome (hereditary amyloid neuropathy), Refsum's disease, Tangierdisease, and others. Causes of acquired peripheral neuropathy addressedby the systems and methods of the present technology include nervecompression, entrapment or laceration (e.g., crutches, ulnar neuropathy,thoracic outlet syndrome, meralgia paresthetica, Morton'smetatarsalgia); metabolic (diabetes mellitus, hypothyroidism) andautoimmune disorders (lupus, rheumatoid arthritis, Guillain-BarreSyndrome, Miller Fisher Syndrome); kidney disease, liver disease,toxin-induced (alcohol, tobacco, asbestos, arsenic, lead, mercury);cancer (e.g., malignant lymphoma, lung cancer, etc.); viral or bacterialinfections (HIV, Lyme disease, leprosy, poliomyelitis);medication-induced (e.g., chemotherapy, etc.); trauma; repetition(carpal tunnel syndrome, cubital tunnel syndrome); and vitamindeficiency (especially vitamin B).

As used herein, “treat” or “treatment” with reference to peripheralneuropathy includes preventing, ameliorating, suppressing, oralleviating one or more of the symptoms of abnormal sensory responsescaused by peripheral neuropathy. In some cases, the treatment protocolsof the present technology result in the reactivation of the nerve (e.g.,restoring the ability of the nerve to depolarize and conduct signals).

As used herein, (the terms “sensory deficit,” “sensory loss,” “abnormalsensory response,” “abnormal sensory function,” etc. refer to allsymptoms caused by disease and/or damage to the peripheral nerves (largeand/or small fiber) of the somatosensory system, such as numbness,decreased responsiveness to light touch, pain, thermal sensation, andvibratory sensation, impaired joint position sense, impaired balance,and decreased muscle strength. The terms “somatosensory” refersgenerally to sensations (such as pressure, pain, or warmth) that canoccur anywhere in the body, as opposed to a particular organ-specificsense, such as sight or smell. The foregoing terms also include“dysesthesia”, an unpleasant and/or abnormal sense of touch, which inturn can include sensations of burning, wetness, itching, electricshock, and/or pins and needles, and which can affect any tissue,including but not limited to the mouth, skin, scalp and/or legs. Whenaddressing or treating somatosensory dysfunction using high-frequencytherapy signals in accordance with the present technology, the therapysignals may well have an effect on the patient's perception of pain—butin a different manner than that associated with existing techniques fortreating chronic pain via high frequency signals. In particular,existing high frequency therapy signal regimens for addressing chronicpain are generally designed to reduce or eliminate pain (e.g., chronic,neuropathic pain). By contrast, when high frequency therapy signals areadministered in accordance with the present technology to address ortreat somatosensory dysfunction, they may operate to improve, restore orat least partly restore the patient's ability to detect and/or perceivepain. Now, if the patient also suffers from chronic pain, the highfrequency therapy signal can be administered in a manner that alsoaddresses (reduces) chronic pain, in addition to addressingsomatosensory deficits.

3.0 Representative Treatment Systems and Associated Methods

FIG. 1 schematically illustrates a representative treatment system 100for treating peripheral neuropathy and/or other sensory deficits,positioned relative to the general anatomy of a patient's spinal columnS. The treatment system 100 can include a signal delivery system 101having a signal generator 102 (e.g., a pulse generator) and a signaldelivery device 103 comprising one or more signal delivery elements 104(referred to individually as first and second signal delivery elements104 a, 104 b, respectively). The signal generator 102 can be connecteddirectly to the signal delivery element(s) 104, or it can be coupled tothe signal delivery element(s) 104 via a signal link 108 (e.g., anextension). In some embodiments, the signal generator 102 may beimplanted subcutaneously within a patient P. As shown in FIG. 1 , thesignal delivery element(s) 104 is configured to be positioned at orproximate to the spinal cord to apply a high frequency electrical signalto the spinal cord (e.g., to the white matter and/or glial cells of thespinal cord). Without being bound by theory, it is believed that glialcells are present in large concentrations within both white and greymatter, and that high frequency modulation at or proximate to the whiteand grey matter can affect electrically deficient glial cells. However,the therapies described herein may provide effective treatment via othermechanisms of action.

In representative embodiments, the signal delivery device 103 includesthe first and second signal delivery elements 104 a, 104 b, each ofwhich comprises a flexible, isodiametric lead or lead body that carriesfeatures or structures, for delivering an electrical signal to thetreatment site after implantation. As used herein, the terms “lead” and“lead body” include any of a number of suitable substrates and/orsupport members that carry structures, for providing therapy signals tothe patient. For example, the lead body can include one or moreelectrodes or electrical contacts that direct electrical signals intothe patient's tissue, such as to directly affect a cellular membrane. Insome embodiments, the signal delivery device 103 and/or signal deliveryelements 104 can include devices other than a lead body (e.g., a paddle)that also direct electrical signals and/or other types of signals to thepatient. Additionally, although FIG. 1 shows an embodiment utilizing twosignal delivery elements 104, in some embodiments the signal deliverysystem 101 and/or signal delivery device 103 can include more or fewersignal delivery elements (e.g., one signal delivery element, 104 threesignal delivery elements 104, four signal delivery elements 104, etc.),each configured to apply electrical signals at different locationsand/or coordinate signal delivery to deliver a combined signal to thesame (or generally the same) anatomical location.

As shown in FIG. 1 , the first signal delivery element 104 a can beimplanted on one side of the spinal cord midline M, and the secondsignal delivery element 104 b can be implanted on the other side of thespinal cord midline M. For example, the first and second signal deliveryelements 104 a, 104 b shown in FIG. 1 may be positioned just off thespinal cord midline M (e.g., about 1 mm offset) in opposing lateraldirections so that the first and second signal delivery elements 104 a,104 are spaced apart from each other by about 2 mm. In some embodiments,the first and second signal delivery elements 104 a, 104 b may beimplanted at a vertebral level ranging from, for example, about T8 toabout T12. In some embodiments, one or more signal delivery devices canbe implanted at other vertebral levels, depending, for example, on thespecific indication for which the patient is being treated.

The signal generator 102 can transmit signals (e.g., electrical therapysignals) to the signal delivery element 104 that up-regulate (e.g.,stimulate or excite) and/or down-regulate (e.g., block or suppress)target nerves (e.g., local vagal nerves). As used herein, and unlessotherwise noted, to “modulate,” “stimulate,” or provide “modulation” or“stimulation” to the target nerves refers generally to having eithertype of the foregoing effects on the target nerves. The signal generator102 can include a machine-readable (e.g., computer-readable) mediumcontaining instructions for generating and transmitting suitable therapysignals. The signal generator 102 and/or other elements of the treatmentsystem 100 can include one or more processors 110, memories 112 and/orinput/output devices 140. Accordingly, the process of providingelectrical signals, detecting physiological parameters of the patient,adjusting the modulation signal, and/or executing other associatedfunctions can be performed by computer-executable instructions containedby computer-readable media located at the signal generator 102 and/orother system components. The signal generator 102 can include multipleportions, elements, and/or subsystems (e.g., for directing signals inaccordance with multiple signal delivery parameters) housed in a singlehousing, as shown in FIG. 1 , or in multiple housings.

The signal delivery system 101 can include one or more sensing elements113 for detecting one or more physiological parameters of the patientbefore, during, and/or after the application of electrical therapysignals. In some embodiments, one or more of the sensing elements 113can be carried by the signal generator 102, the signal delivery element104, and/or other implanted components of the system 101. In someembodiments, the sensing element 113 can be an extracorporeal orimplantable device separate from the signal generator 102 and/or signaldelivery element 104. Representative sensing elements 113 include one ormore of: a subcutaneous sensor, a temperature sensor, an impedancesensor, a chemical sensor, a biosensor, an electrochemical sensor, ahemodynamic sensor, an optical sensor and/or other suitable sensingdevices. Physiological parameters detected by the sensing element(s) 113include neurotransmitter concentration, local impedance, current, and/orvoltage levels, and/or any correlates and/or derivatives of theforegoing parameters (e.g., raw data values, including voltages and/orother directly measured values).

The signal generator 102 can also receive and respond to one or moreinput signals received from one or more sources. The input signals candirect or influence the manner in which the therapy and/or processinstructions are selected, executed, updated, and/or otherwiseperformed. The input signals can be received from one or more sensors(input devices, 140 (e.g., the sensor 113) shown schematically in FIG. 1for purposes of illustration) that are carried by the signal generator102 and/or distributed outside the signal generator 102 (e.g., at otherpatient locations) while still communicating with the signal generator102. The sensor 113 and/or other input devices 140 can provide inputsthat depend on or reflect patient state (e.g., patient position, patientposture, and/or patient activity level), and/or inputs that arepatient-independent (e.g., time). Still further details are included inU.S. Pat. No. 8,355,797, which is incorporated herein by reference.

In some embodiments, the signal generator 102 can obtain power togenerate the therapy signals from an external power source 114. Theexternal power source 114 can transmit power to the implanted signalgenerator 102 using electromagnetic induction (e.g., RF signals). Forexample, the external power source 114 can include an external coil 116that communicates with a corresponding internal coil (not shown) withinthe implantable signal generator 102. The external power source 114 canbe portable for ease of use.

In some embodiments, the signal generator 102 can obtain the power togenerate therapy signals from an internal power source, in addition toor in lieu of the external power source 114. For example, the implantedsignal generator 102 can include a non-rechargeable battery or arechargeable battery to provide such power. When the internal powersource includes a rechargeable battery, the external power source 114can be used to recharge the battery. The external power source 114 canin turn be recharged from a suitable power source (e.g., conventionalwall power).

During at least some procedures, an external generator 120 (e.g., atrial stimulator or modulator) can be coupled to the signal deliveryelement 104 during an initial procedure, prior to implanting the signalgenerator 102. For example, a practitioner (e.g., a physician and/or acompany representative) can use the external generator 120 to providetherapy signals and vary the modulation parameters provided to thesignal delivery elements 104 in real time, and select optimal orparticularly efficacious parameters. These parameters can include thelocation from which the electrical signals are emitted, as well as thecharacteristics of the electrical signals provided to the signaldelivery elements 104. In some embodiments, input is collected via theexternal generator 120 and can be used by the clinician to helpdetermine what parameters to vary. In a typical process, thepractitioner uses a cable assembly 128 to temporarily connect theexternal generator 120 to the signal delivery element 104. Thepractitioner can test the efficacy of the signal delivery elements 104in an initial position. The practitioner can then disconnect the cableassembly 128 (e.g., at a connector 130), reposition the signal deliveryelements 104, and reapply the electrical signal. This process can beperformed iteratively until the practitioner obtains the desired signalparameters and/or position for the signal delivery element 104.Optionally, the practitioner can move the partially implanted signaldelivery element 104 without disconnecting the cable assembly 128.Furthermore, in some embodiments, the iterative process of repositioningthe signal delivery elements 104 and/or varying the therapy parametersmay not be performed. Instead, the practitioner can place signaldelivery element(s) 104 at an approximate anatomical location, and thenselect which electrodes or contacts deliver the therapy signal, as a wayof varying the location to which the therapy signal is directed, withoutrepositioning the signal delivery element(s).

After the signal delivery elements 104 are implanted, the patient P canreceive therapy via signals generated by the external generator 120,generally for a limited period of time. During this time, the patientwears the cable assembly 128 and the external generator outside thebody. Assuming the trial therapy is effective or shows the promise ofbeing effective, the practitioner then replaces the external generator120 with the implanted signal generator 102, and programs the signalgenerator 102 with therapy programs selected based on the experiencegained during the trial period. Optionally, the practitioner can alsoreplace the signal delivery elements 104. The signal delivery parametersprovided by the signal generator 102 can still be updated after thesignal generator 102 is implanted, via a wireless physician's programmer124 (e.g., a physician's remote) and/or a wireless patient programmer126 (e.g., a patient remote). Generally, the patient P has control overfewer parameters than does the practitioner. For example, the capabilityof the patient programmer 126 may be limited to starting and/or stoppingthe signal generator 102, and/or adjusting the signal amplitude. Thepatient programmer 126 may be configured to accept pain relief input aswell as other variables, such as medication use.

The signal generator 102, the lead extension, the external programmer120 and/or the connector 130 can each include a receiving element 109.Accordingly, the receiving elements 109 can be implantable elements(implantable within the patient), or the receiving elements 109 can beintegral with an external patient treatment element, device or component(e.g., the external generator 120 and/or the connector 130). Thereceiving elements 109 can be configured to facilitate a simple couplingand decoupling procedure between the signal delivery elements 104, thelead extension, the signal generator 102, the external generator 120,and/or the connector 130. The receiving elements 109 can be at leastgenerally similar in structure and function to those described in U.S.Patent Application Publication No. 2011/0071593.

FIG. 2 is a cross-sectional illustration of a spinal cord SC and anadjacent vertebra VT (based generally on information from Crossman andNeary, “Neuroanatomy,” 1995 (published by Churchill Livingstone)), alongwith multiple signal delivery elements 104 (shown as signal deliveryelements 104 a-104 f) implanted at representative locations. Forpurposes of illustration, multiple signal delivery elements 104 areshown in FIG. 2 implanted in a single patient. In actual use, any givenpatient will likely receive fewer than all the signal delivery elements104 shown in FIG. 2 .

As shown in FIG. 2 , the spinal cord SC is situated within a vertebralforamen F, between a ventrally located ventral body VB and a dorsallylocated transverse process TP and spinous process SP. Arrows V and Didentify the ventral and dorsal directions, respectively. The spinalcord SC itself is located within the dura mater DM, which also surroundsportions of the nerves exiting the spinal cord SC, including the ventralroots VR, dorsal roots DR and dorsal root ganglia DRG. The dorsal rootsDR enter the spinal cord SC at the dorsal root entry zone E, andcommunicate with dorsal horn neurons located at the dorsal horn DH. Inone embodiment, the first and second signal delivery elements 104 a, 104b are positioned just off the spinal cord midline M (e.g., about 1 mmoffset) in opposing lateral directions so that the two signal deliveryelements 104 a, 104 b are spaced apart from each other by about 2 mm. Inother embodiments, a lead or pairs of leads can be positioned at otherepidural locations, e.g., toward the outer edge of the dorsal root entryzone E as shown by a third signal delivery element 104 c, or at thedorsal root ganglia DRG, as shown by a fourth signal delivery element104 d, or approximately at the spinal cord midline M, as shown by afifth signal delivery element 104 e, or near the ventral roots, as shownby a sixth signal delivery element 104 f. In some embodiments, the leadsare positioned near the exit of the ventral roots may be advantageous tomodify ventral motor pools located in the gray matter. For example,modification of these ventral motor pools may treat spasticity, motordisorders and/or other disorders arising from the ventral motor pools.

In some embodiments, it may be advantageous to position one or moresignal delivery elements 104 within the dura mater DM to target neuraltissue and one or more glial cells present in the gray and white matterof the spinal cord SC. For example, as shown in the cross-sectional viewof a spinal cord SC in FIG. 3 , in some embodiments a seventh signaldelivery element 104 g and an eighth signal delivery element 104 i arepositioned along the spinal cord midline M on the dorsal and ventralsides of the spinal cord SC, respectively. In some embodiments, one ormore signal delivery elements 104 can be positioned at other locations.For example, in some embodiments a ninth signal delivery element 104 hand a tenth signal delivery element 104 j are positioned off the spinalcord midline M on opposing lateral sides of the spinal cord SC. Highfrequency signals applied to the tenth signal delivery element 104 j maybe especially effective at reducing sympathetic outflow. In someembodiments, high frequency signals applied to the tenth signal deliveryelement 104 j may treat heart failure, hypertension, complex regionalpain syndrome, peripheral vascular disease, and other diseases whereelevated sympathetic tone is implicated. In some embodiments, one ormore signal delivery elements 104 may be positioned in other suitablelocations within the subdural space. Additionally, in some embodiments,a physician may position one or more signal delivery elements in theepidural space and one or more signal delivery elements in the subduralspace. More generally any one of the foregoing signal delivery elementsmay be used alone or in combination with any other signal deliveryelement(s) 104, depending upon the patent indication(s).

4.0 Representative Clinical Data

FIG. 4 is a table 400 of selected clinical data gathered duringApplicant's clinical study in which patients were implanted with one ormore signal delivery elements in accordance with the devices, systems,and methods described in under heading 3.0 above. In particular,patients received electrical therapy signals at a frequency of 10 kHz, apulse width of 30 microseconds, and an amplitude that ranged from about0.5 mA to about 6 mA.

Table 400 includes the following acronyms/abbreviations:

-   -   SCI—spinal cord injury    -   ITP—Intrathecal pump    -   UL—Upper Limb    -   R—Right    -   SC—Spinal cord    -   MA program—Multi-area program    -   LBP—Low back pain

As shown in the first row of the table 400, Patient 1 suffered fromupper and lower back pain caused by a spinal cord injury at the eighththoracic vertebrae. Patient 1 was paraplegic and presented withdystonia, spasms (“dancing legs”), and low back and chest wall pain.Before treatment, Patient 1 was able to sit comfortably for only 10-15minutes. Based on Patient 1's pain location (lower and upper back), thelead electrodes were placed at or between the eighth and the elevenththoracic vertebrae (T8-T11). After treatment, Patient 1's spasms weregone, and Patient 1 was able to sit for several hours.

As shown in the second row of table 400, Patient 2 suffered fromthoracic pain caused by a cervical spinal cord injury. Patient 2presented with a paralyzed leg, and spasticity. Before treatment,Patient 2 required a crutch for walking. Based on Patient 2's painlocation (thoracic), the lead electrodes were placed at or near thevertical midpoint of the second thoracic vertebrae (T2). Aftertreatment, Patient 2 had improved movement (i.e., improved “tone”, andwas able to walk smoothly), renewed functional capacity in the paralyzedleg, a reduction in thoracic pain, improvement in spasticity, and wasable to transition from seated to standing positions that caused spasmsor tone problems before treatment.

As shown in the third row of table 400, Patient 3 suffered from low backpain caused by a partial spinal cord injury with significant damage atthe ninth and tenth thoracic vertebra (T9-T10). Patient 3 was paraplegicand also presented with migraines. Based on Patient 3's painindications, the lead electrodes were placed at the third cervicalvertebrae (C3). Patient 3's migraine and low back pain were successfullytreated. After treatment, Patient 3's ability to sense slight itchingwas restored, and Patient 3 was able to sense pinpricks in the legs aslong as the high frequency stimulation was being delivered. Patient 3was also able to flex both ankles in dorsi- and plantar-flexion, bendhis legs at both knees, stand up and bear weight with support, and hadspontaneous return of erectile function.

As shown in the fourth row of table 400, Patient 4 presented with footpain from small fiber neuropathy (peripheral neuropathy) and could notsense a pin-prick sensation in that foot. Patient 4 presented withBabinski reflex, severe and constant muscle spasms in the back, constantburning sensation at the skin, and stabbing pain in the low- andmid-back. Based on Patient 4's pain indication, the lead electrodes wereplaced to span from the superior aspect of the eighth thoracic vertebrae(T8) to the superior aspect of the twelfth thoracic vertebrae (T12).After treatment, Patient 4 experienced restored pin-prick sensations inthe foot, the Babinski reflex disappeared and the patient experiencedreduced pain in the foot.

As shown in the fifth row of table 400, Patient 5 presented with no pinprick sensation. After a trial period, Patient 5 had restored pin pricksensation in the feet. Sensation was maintained at follow-up visits. Tenadditional patients (not represented in table 400) also presented withno pin prick sensation, and also had their pinprick sensation restoredfollowing treatment in accordance with the foregoing parameters(frequency of 10 kHz, a pulse width of 30 microseconds, and an amplitudethat ranged from about 0.5 mA to about 6 mA). These cases, as well asothers discussed herein, are representative of patients recoveringpain-based sensory responses via a high frequency electrical therapy.

An additional patient, not represented in table 400, was a paraplegicSCI patient, with a lesion at T11 and with neuropathic lower back pain.His T10-L2 vertebral bodies were fused as a result of injury. Followingseveral failed (more conservative) therapies, he received a highfrequency therapy regimen in accordance with the foregoing parametersvia a single lead positioned epidurally between the T10-L1 vertebralbodies. In general, leads for high frequency therapy are placed atT8-T11 for back pain, but in this case, the lead could not be advanced(in a rostral direction) past mid-T10. The patient had a dural punctureduring the procedure and the resulting headache prevented accuratereporting of pain scores for the first two days of the trial period.However, by the third day, the patient reported significant back painrelief. At the end of the seven day trial period, the patient reported80% pain relief and was able to voluntarily move his leg for the firsttime in 15 years. Sensation to touch and pin prick were restored fromthe L1-S1 dermatomes. His neurological status improved from spasticparalysis at baseline to non-spastic weakness. In addition, for the lastthree days of the trial, the patient had regained micturition controland had stopped self-catheterizing.

The electrical therapy treatment methods of the present technology maybe used with other therapies (e.g., conventional therapies) forperipheral neuropathy treatment. Such therapies include, but not limitedto: corticosteroids; IV immunoglobulins; plasma exchange orplasmapheresis; immunosuppressive agents; surgery; mechanical aids;avoiding toxins including alcohol; aldose reductase inhibitors; fishoil; gamma-linolenic acid; gangliosides; lipoic acid; myoinositol; nervegrowth factor; protein kinase C inhibitors; pyridoxine; ruboxistaurinmesylate; thiamine; vitamin B12; pain relievers including codeine;anti-seizure medications including gabapentin, topiramate, pregabalin,carbamazepine, and phenytoin; topical anesthetics such as lidocaine;tricyclic antidepressant medications such as amitriptyline andnortriptyline; selective serotonin and norepinephrine reuptakeinhibitors such as duloxetine; and mexiletine. The agents may alsoinclude, for example, dopamine uptake inhibitors, monoamine oxidaseinhibitors, norepinephrine uptake inhibitors, dopamine agonists,acetocholinesterase inhibitors, catechol O-methyltransferase inhibitors,anticholinergic agents, antioxidants, as well as synaptic and axonalenhancing medications. Additionally, it has been observed that HFtherapy can reduce the need for supplemental medications. For example,in a randomized controlled trial of HF therapy for low back and legpain, concomitant morphine-equivalent medication use and dosage weresignificantly reduced. Thus, in the context of the present technology,those agents used as primary, supplemental, or adjuvant treatments canbe reduced, bringing the benefit of both reduced side-effects andpatient compliance burden, when HF therapy is successfully applied.

Further Clinical Results

The following sections described further clinical results obtained bytreating patients with therapy signals at frequencies in the range of1.5 kHz to 100 kHz.

(a) Peripheral Polyneuropathy

FIGS. 5A-5C illustrate data obtained from six peripheral polyneuropathypatients, all presenting with bilateral lower extremity pain. Each ofthe patients was treated with a therapy signal at 10 kHz, applied to thepatient at the T8-T11 vertebral level. The signal had a pulse width of30 microseconds, and an amplitude that varied from patient to patient.As shown in FIG. 5A, three patients were diagnosed with diabeticperipheral neuropathy, two patients with idiopathic peripheralneuropathy, and one patient with chronic inflammatory demyelinatingpolyneuropathy. Five of the six patients experienced at least a 50%reduction in pain during an approximately one week trial period, and allwere implanted with a pulse generator and signal delivery device.

As shown in FIG. 5B, four of the five patients who received medicationprior to receiving treatment via the 10 kHz therapy signal had theirmedication reduced or eliminated. As is also shown in FIG. 5B, severalof the patients also reported an improvement in sensation level relativeto baseline.

FIG. 5C illustrates the pain scores of the patients at baseline, at theend of the temporary trial, and as of a subsequent follow-up (10.7months, plus or minus 6 months). These data indicate that the patientsreceived a significant reduction in pain, which was sustained over asignificant period after the trial period.

Anecdotally, an additional diabetic patient (not included in the datashown in FIGS. 5A-5C) suffered a significant amount of pain in his lowerlegs, which were ulcerated. He was near to receiving an amputation ofhis leg, prior to receiving electrical signal therapy at 10 kHz via animplanted stimulation device in accordance with the foregoingparameters. After stimulation for a period of two months, the patient'spain was reduced, the patient's wounds were healing, the color returnedto the patient's legs, and the patient was walking, whereas previouslythe patient had been in a wheelchair.

(b) Post-Stroke Pain

In still a further example, patients were treated for centralpost-stroke pain (CPSP). CPSP refers to chronic neuropathic painresulting from lesions of the central somatosensory nervous system,particularly the spinothalamocortical pathway. The prevalence of CPSP is1-12% in stroke patients, and symptom onset usually occurs within sixmonths. Most patients complain of burning, allodynia, and hyperalgesia.CPSP is typically pharmacoresistant, and therapeutic options forrefractory cases are limited.

An 85-year-old male with a prior history of hypertension, pre-diabetes,and stroke presented for management of right lower extremity (RLE) pain.One year earlier, he had presented with a new left-sided weakness.Following a stroke diagnosis, he underwent intensive rehabilitation andhad near complete resolution of left hemibody weakness. However, sixmonths later, he began to experience new RLE pain. Workup for re-strokewas negative. The patient's pain was constant and burning, with anaverage intensity of 8 on a numerical rating scale of 0-10 for painassessment, and associated with allodynia and hyperalgesia. He receivedno benefit from amitriptyline, physical therapy or a right lumbarsympathetic block.

The patient received spinal cord stimulation at 10 kHz, with a signaldelivery device spanning the T8-T11 vertebral bodies. The patientreceived a successful trial and then underwent permanent implantation.At an 8-week follow-up, he reported greater than 80% pain relief, withan average pain score of 2 and significant improvement in his quality oflife. Based at least upon this patient's outcome, it is believed thatstimulation in accordance with the foregoing parameters can proveeffective for medically refractory CPSP.

(c) Foot Drop

In another example, two patients presented with both chronic low backpain, and bilateral foot drop following complications from prior spinalsurgeries. Patient 1, a 62-year-old woman, experienced persistent footdrop for 13 years, ambulating with aides.

Electromyogram (EMG) tests revealed mild sensorimotor axonalpolyneuropathy, with demyelinating features. The patient was affected bychronic neurogenic deficits affecting vertebral levels L4-L5 and S1bilaterally, with active denervation affecting the L5 root on the rightside. The patient had been prescribed with analgesics for control ofpain at a level of 8 out of 10 on the numerical rating scale, whichinduced unpleasant side effects.

Patient 2 was a 45-year-old male who suffered from acute paraplegiacomplications following spinal surgery. His neurological deficitgradually improved, but his back pain and bilateral lower extremityweakness remained, with this right side worse, resulting in anankle-foot orthosis. Arachnoiditis was evident at the L4-L5 level, withsignificant clumping of the nerve roots at this level. The patientreceived strong analgesics for his back pain, which was at a level of5-8/10 on the numerical rating scale.

After receiving stimulation at 10 kHz during a trial, both patientsproceeded to a permanent implant at a vertebral level of T8-T11. Bythree months post-implant, both patients no longer required orthotics,and began weaning opioids. At six months, Patient 1's foot drop hadcompletely resolved, with a return of sensation and no pain. At ninemonths, Patient 1 had weaned off opioids completely, reportingsignificant improvements in function without aides, and was able todrive a car. Patient 2 no longer used opioids at six monthspost-implant, and reported almost complete resolution of his foot drop.In addition, Patient 2 reported an average pain score of one on a scaleof ten, improved walking, and the ability to ride a bicycle.

It is expected that dorsally positioned electrodes can provide theforegoing motor benefits. For example, dorsal white matter tracts feedinto spinal grey matter circuits to inhibit/facilitate reflex and motorcoordination. In pathologic states, or in the absence of descendingcontrol, these circuits may become dysfunctional, e.g., spastic, tonic,and/ or dis-coordinated. HF therapy can ‘normalize’ these circuits viagrey matter and/or glial effects, to restore patient function andactivities of daily living.

(d) Dysesthesia

In still further example, several patients suffering from dysesthesiawere treated with spinal cord stimulation at a frequency of 10 kHz, apulse width of 30 microseconds, and a current amplitude that varied frompatient to patient. Prior to treatment, the patients were diagnosed withperipheral polyneuropathy and/or painful diabetic neuropathy. Somepatients experienced the inability to feel the bottoms of their feet,which created balance and gait issues, and some patients experiencedfoot numbness and tingling. After 6-7 days of receiving therapy at 10kHz, the foot numbness and tingling disappeared, and the patientsexperienced an improvement in gait.

The foregoing gait and sensory improvements can be particularlysignificant for patients suffering from diabetes, because when suchpatients can walk, they are better able to control their blood sugar.Patients are also better able to avoid falls and fractures, which areadditional issues associated with diabetic patients.

Based on the foregoing, it is expected that stimulation in accordancewith the foregoing parameters can be used to address lower limb pain,foot and ankle pain, other types of focal, neuropathic pain, and/ordysesthesia. These results are expected to be achieved with spinal cordstimulation delivered at 10 kHz or other high frequency values, to thedorsal column of the patient's spinal cord. This is contrary toconventional techniques, which may require that stimulation be appliedto the dorsal root ganglion.

In addition, based on the foregoing results, stimulation in accordancewith the parameters disclosed herein can produce benefits in additionto, or in lieu of, pain reduction. Such benefits involve restoration ofsensory and/or motor functions.

Further Indications

The discussion above describes representative therapies in the contextof treatment for spinal cord injury, peripheral neuropathy and otherindications. In some embodiments, the therapy can be administered topatients with peripheral polyneuropathy indications. More generally, thetherapy can be applied to patients with other indications, otherindications that are associated with sensory loss, and/or motordeficits. As an example, in at least some cases, the observed sensoryimprovement is correlated (e.g., other indications directly orindirectly) with motor improvement. Accordingly, the foregoingtechniques can be used to facilitate sensory and/or motor functionrecovery. In particular, at least one patient (Patient 2 described abovewith reference to FIG. 4 ) experienced a reduction in spasticity, aswell as other motor-related improvements, in addition to a reduction inpain.

It is expected that, in at least some embodiments, the foregoingtherapies can be used to address sensory deficit, and/or motor deficit,and/or spinal cord injury, in combination with treating pain. In someembodiments, the foregoing therapies can be used to address sensorydeficit, and/or motor deficit, and/or spinal cord injury, independent ofwhether or not the therapy is also used to treat pain. In at least someembodiments, the target location of the therapy signal may be different,depending on whether the therapy is used to address pain, or one or moreof a sensory deficit, motor deficit, or spinal cord injury. For example,in at least some cases, it was found that therapy delivered to treatsegmental pain also produced an improvement in sensory response, but ata location rostral or caudal to the segmental pain indication.

It is also believed that sensory deficit can be reversed when treatingpolyneuropathy, without moving the therapy treatment site, and that footpain can be addressed with a more generalized treatment location (e.g.,T8-T12), as opposed to a specific location (such as the DRG at L5 orS1). More generally, it is believed that the therapy can be applied tothe spinal cord instead of the DRG (which is where at least someconventional low frequency treatments are applied). Advantages ofapplying the therapy signal to the spinal cord rather than the DRGinclude (a) a lower incidence of adverse events/safety concerns, and/or(b) a broader electric field spread that may have additional pain and/orother benefits, whereas DRG stimulation is typically very focal. Inaddition, implanting the signal delivery device at the spinal cord maybe simpler and easier to “standardize” than implanting the signaldelivery device at the DRG.

Several embodiments of the present technology were described above inthe context of therapy signals applied to the patient's spinal cordregion. In other embodiments, the therapy signal may be applied to otherlocations, e.g., peripheral locations.

Without being bound by theory, it is possible that treating motor andsensory deficits may result from different mechanisms of action. Forexample, it may be that hyperpolarization of the lamina I/IIinterneurons explains the resolution of spastic/dystonic (motor)symptoms (e.g., caused by a barrage of spontaneous firing), and thetherapies described above hyperpolarize those cells resulting areduced/normalized neuronal activity level. Because sensory deficit maybe due to lack of input from neurons, the ability to address sensorydeficit as well as motor symptoms via the same therapy signal may be anindication that different mechanisms of action are responsible for eachresult. For example, the beneficial effect on motor symptoms may resultfrom a reversal of inhibition or hyperpolarization. Alternatively, thenormalization of the sensory input may be the cause of a reduced motordysfunction. In other words, the sensorimotor reflex may be returned tonormal when the sensory neuron returns to normal.

Representative Signal Delivery Parameters

The therapy signals described above may be delivered in accordance withseveral suitable signal delivery parameters. For example, the signalfrequency may be from about 1.2 kHz to about 100 kHz, or from about 1.5kHz to about 100 kHz, or from about 2 kHz to about 50 kHz, or from about3 kHz to about 20 kHz, or from about 3 kHz to about 15 kHz, or fromabout 5 kHz to about 15 kHz, or from about 3 kHz to about 10 kHz, or 1kHz, 2 kHz, 3 kHz, 4 kHz, 5 kHz, 10 kHz, 15 kHz, 20 kHz, 50 kHz, or 100kHz. In particular embodiments, representative current amplitudes forthe therapy signal are from 0.1 mA to 20 mA, or 0.5 mA to 10 mA, or 0.5mA to 7 mA, or 0.5 mA to 5 mA. Representative pulse widths range fromabout 10 to about 333 microseconds, about 10 to about 166 microseconds,about 25 to about 166 microseconds, about 20 to about 100 microseconds,about 30 to about 100 microseconds, about 30 to about 40 microseconds,about 10 to about 50 microseconds, about 20 to about 40 microseconds,about 25 to about 35 microseconds, about 30 to about 35 microseconds,and about 30 microseconds. Duty cycles can range from about 10% to about100%, and in a particular duty cycle, signals are delivered for 20seconds and interrupted for 2 minutes (an approximate 14% duty cycle).In other embodiments, these parameters can have other suitable values.Other suitable parameters and other therapy features are disclosed inthe following materials, each of which is incorporated by reference:U.S. Patent Application Publication No. US2009/0204173; U.S. PatentApplication Publication No. US2014/0296936; and U.S. Patent ApplicationPublication No. US2010/0274314.

From the foregoing, it will be appreciated that specific embodiments ofthe disclosed technology have been described herein for purposes ofillustration, but that various modifications may be made withoutdeviating from the technology. Certain aspects of the technologydescribed in the context of particular embodiments may be combined oreliminated in other embodiments. Further, while advantages associatedwith certain embodiments of the disclosed technology have been describedin the context of those embodiments, other embodiments may also exhibitsuch advantages, and not all embodiments need necessarily exhibit suchadvantages to fall within the scope of the technology. Accordingly, thedisclosure and associated technology can encompass other embodiments notexpressly shown or described herein. The following examples providefurther representative embodiments of the presently disclosedtechnology.

As used herein, the phrase “and/or,” as in “A and/or B” refers to Aalone, B alone, and A and B. To the extent any materials incorporated byreference herein conflict with the present disclosure, the presentdisclosure controls.

1-30. (canceled)
 31. A method of treating a patient having diabeticneuropathy, via spinal cord stimulation, comprising: at least partiallyin response to the patient having a symptom of tingling caused by thepatient's diabetic neuropathy, programming a signal generator to delivera non-paresthesia producing electrical signal to the patient's spinalcord via at least one implanted signal delivery element, wherein thenon-paresthesia producing electrical signal has a frequency of 10 kHz, apulse width in a pulse width range of from about 30 microseconds toabout 35 microseconds, and an amplitude in an amplitude range of from0.5 mA to 7 mA, wherein the non-paresthesia producing electrical signalat least partially eliminates the tingling caused by the diabeticneuropathy without causing a side-effect of signal-induced paresthesia.32. The method of claim 31 wherein the at least one implanted signaldelivery element is positioned in the patient's thoracic vertebralregion.
 33. The method of claim 31 wherein the at least one implantedsignal delivery element is positioned in the patient's thoracicvertebral region between T8 and T12, inclusive.
 34. The method of claim31 wherein the at least one implanted signal delivery element ispositioned in the patient's epidural space.
 35. The method of claim 31wherein the tingling is in the patient's foot.
 36. The method of claim31 wherein the patient also has foot pain caused by the patient'sdiabetic neuropathy, and wherein the non-paresthesia producingelectrical signal also reduces the patient's foot pain without causingthe side-effect of signal-induced paresthesia.
 37. The method of claim36 wherein programming the signal generator is performed at leastpartially in response to the patient having foot pain.
 38. A method oftreating a patient having diabetic neuropathy, via spinal cordstimulation, comprising: at least partially in response to the patienthaving a symptom of tingling associated with the patient's diabeticneuropathy, programming a signal generator to deliver a non-paresthesiaproducing electrical signal to the patient's spinal cord via at leastone implanted signal delivery element, wherein thenon-paresthesia-producing electrical signal has a frequency in afrequency range of from about 5 kHz to about 15 kHz, a pulse width in apulse width range of from about 20 microseconds to about 40microseconds, and an amplitude in an amplitude range of from 0.5 mA to10 mA, wherein the non-paresthesia producing electrical signal at leastpartially eliminates the tingling associated with the diabeticneuropathy without causing a side-effect of signal-induced paresthesia.39. The method of claim 38 wherein the at least one implanted signaldelivery element is positioned in the patient's epidural space at athoracic vertebral region between T8 and T12, inclusive.
 40. The methodof claim 38 wherein the non-paresthesia producing electrical signal hasa duty cycle of between about 10% and about 100%.
 41. The method ofclaim 40 wherein the non-paresthesia producing electrical signal has aduty cycle of about 14%.
 42. The method of claim 38 wherein the tinglingis concentrated in one or both of the patient's feet and/or one or bothof the patient's hands.
 43. The method of claim 38 wherein the signalgenerator is implanted.
 44. A method of treating a patient havingdiabetic neuropathy, via spinal cord stimulation, comprising: at leastpartially in response to the patient having tingling associated with thepatient's diabetic neuropathy, programming a signal generator to delivera non-paresthesia producing electrical signal to the patient's spinalcord via at least one implanted signal delivery element, wherein thenon-paresthesia producing electrical signal has a frequency in afrequency range of from about 1.5 kHz to about 20 kHz, a pulse width ina pulse width range of from about 20 microseconds to about 100microseconds, and an amplitude in an amplitude range of from 0.5 mA to10 mA, wherein the non-paresthesia producing electrical signal at leastpartially eliminates the tingling associated with the diabeticneuropathy without causing a side-effect of signal-induced paresthesia.45. The method of claim 44 wherein the at least one implanted signaldelivery element is positioned at a thoracic vertebral region between T8and T12, inclusive.
 46. The method of claim 44 wherein thenon-paresthesia producing electrical signal has a duty cycle of betweenabout 10% and about 100%.
 47. The method of claim 46 wherein thenon-paresthesia producing electrical signal has a duty cycle of about14%.
 48. The method of claim 44 wherein the tingling is in one or bothof the patient's feet.
 49. The method of claim 44 wherein the signalgenerator is implanted.
 50. The method of claim 44 wherein the signalgenerator is external.